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A phase Ib study investigating the combination of everolimus and dovitinib in vascular endothelial growth factor refractory clear cell renal cancer

A phase Ib study investigating the combination of everolimus and dovitinib in vascular endothelial growth factor refractory clear cell renal cancer
A phase Ib study investigating the combination of everolimus and dovitinib in vascular endothelial growth factor refractory clear cell renal cancer
Background

Everolimus (mammalian target of rapmaycin (mTOR) inhibitor) and dovitinib (vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF-2) inhibitor) demonstrate activity in metastatic clear cell renal cancer. The combination of these agents has a broad spectrum of relevant activity. The combination is explored in this phase Ib study.

Methods

Patients with metastatic clear cell renal cancer who have failed VEGF targeted therapy were eligible. Up to four cohorts of three to six patients (3+3 design) were treated with escalating doses of everolimus and dovitinib. Dose-limiting toxicities (DLTs) were assessed to determine the maximum tolerated dose (MTD). An expansion cohort (n = 15) was investigated to obtain additional efficacy information. Sequential fluorodeoxyglucose positron emission tomography (FDG-PET) was used as a surrogate marker of response.

Results

Overall 18 patients were recruited into the study. Fifteen patients received the MTD, which was everolimus 5 mg orally (PO) once daily (OD) and dovitinib 200 mg PO day 1–5/7. The MTD was associated with toxicity, which included fatigue, mucositis and diarrhoea in 73%, 53% and 53% (Common Toxicity Criteria (CTC) grade 1–4) of patients, respectively. Frequent biochemical abnormalities occurred (such as hypertriglyceridaemia in 67%). Higher doses of the combination were not tolerable due to grade 3 fatigue in 2/3 patients and grade 3 nausea in 1/3 patients within 1 month of therapy. The response rate at the MDT was 1/15 (7%) while the progression free survival for the MTD was 7 months (95% confidence interval (CI) 2.2–11 months). Pharmacokinetic data at the MTD showed stable kinetics with time.

Conclusion

Dovitinib and everolimus had modest activity, but did not meet all of the planned efficacy end-points. Fatigue was the dose limiting toxicity.
0959-8049
2057-2064
Powles, Thomas
55539b87-1c5e-45ae-9e07-5b2232c2236c
Foreshew, Shah-Jalal Sarker
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Shamash, Jonathan
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Sarwar, Naveed
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Crabb, Simon
bcd1b566-7677-4f81-8429-3ab0e85f8373
Sahdev, Anju
f1eacb5f-58ee-4811-900a-02106411ad4f
Nixon, Jude
6215a395-59cb-4f70-8b8f-8774c325b523
Lim, Louise
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Pungaliya, Ashish
bd38fea9-2adc-4200-be0e-dac53e719c81
Foreshaw, Abigail
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Davies, Rachel
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Greenwood, Michelle
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Wilson, Peter
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Pacey, Simon
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Galazi, Myra
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Jones, Robert
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Chowdhury, Simon
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Powles, Thomas
55539b87-1c5e-45ae-9e07-5b2232c2236c
Foreshew, Shah-Jalal Sarker
04c7ecb5-ae30-4095-b91b-03248761c912
Shamash, Jonathan
6f861cb2-e182-4403-b232-2655c2027cf0
Sarwar, Naveed
0507a5e9-ca62-4dc9-9b56-45968fccbf12
Crabb, Simon
bcd1b566-7677-4f81-8429-3ab0e85f8373
Sahdev, Anju
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Nixon, Jude
6215a395-59cb-4f70-8b8f-8774c325b523
Lim, Louise
baa0ef66-6114-4d91-a3dc-0e330ef22994
Pungaliya, Ashish
bd38fea9-2adc-4200-be0e-dac53e719c81
Foreshaw, Abigail
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Davies, Rachel
d28b6cc1-dccd-45cf-9249-346be72072ae
Greenwood, Michelle
8991a8d2-bf92-411c-82ef-94afc4ac7e52
Wilson, Peter
0bb420af-a54f-4dcc-9564-da53a4e0ef9e
Pacey, Simon
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Galazi, Myra
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Jones, Robert
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Chowdhury, Simon
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Powles, Thomas, Foreshew, Shah-Jalal Sarker, Shamash, Jonathan, Sarwar, Naveed, Crabb, Simon, Sahdev, Anju, Nixon, Jude, Lim, Louise, Pungaliya, Ashish, Foreshaw, Abigail, Davies, Rachel, Greenwood, Michelle, Wilson, Peter, Pacey, Simon, Galazi, Myra, Jones, Robert and Chowdhury, Simon (2014) A phase Ib study investigating the combination of everolimus and dovitinib in vascular endothelial growth factor refractory clear cell renal cancer. European Journal of Cancer, 50 (12), 2057-2064. (doi:10.1016/j.ejca.2014.04.021). (PMID:24908540)

Record type: Article

Abstract

Background

Everolimus (mammalian target of rapmaycin (mTOR) inhibitor) and dovitinib (vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF-2) inhibitor) demonstrate activity in metastatic clear cell renal cancer. The combination of these agents has a broad spectrum of relevant activity. The combination is explored in this phase Ib study.

Methods

Patients with metastatic clear cell renal cancer who have failed VEGF targeted therapy were eligible. Up to four cohorts of three to six patients (3+3 design) were treated with escalating doses of everolimus and dovitinib. Dose-limiting toxicities (DLTs) were assessed to determine the maximum tolerated dose (MTD). An expansion cohort (n = 15) was investigated to obtain additional efficacy information. Sequential fluorodeoxyglucose positron emission tomography (FDG-PET) was used as a surrogate marker of response.

Results

Overall 18 patients were recruited into the study. Fifteen patients received the MTD, which was everolimus 5 mg orally (PO) once daily (OD) and dovitinib 200 mg PO day 1–5/7. The MTD was associated with toxicity, which included fatigue, mucositis and diarrhoea in 73%, 53% and 53% (Common Toxicity Criteria (CTC) grade 1–4) of patients, respectively. Frequent biochemical abnormalities occurred (such as hypertriglyceridaemia in 67%). Higher doses of the combination were not tolerable due to grade 3 fatigue in 2/3 patients and grade 3 nausea in 1/3 patients within 1 month of therapy. The response rate at the MDT was 1/15 (7%) while the progression free survival for the MTD was 7 months (95% confidence interval (CI) 2.2–11 months). Pharmacokinetic data at the MTD showed stable kinetics with time.

Conclusion

Dovitinib and everolimus had modest activity, but did not meet all of the planned efficacy end-points. Fatigue was the dose limiting toxicity.

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More information

Accepted/In Press date: 21 April 2014
e-pub ahead of print date: 4 June 2014
Published date: August 2014
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 365795
URI: http://eprints.soton.ac.uk/id/eprint/365795
ISSN: 0959-8049
PURE UUID: f7c1e98b-6d00-469d-9d4a-992dd20e39ef
ORCID for Simon Crabb: ORCID iD orcid.org/0000-0003-3521-9064

Catalogue record

Date deposited: 19 Jun 2014 10:11
Last modified: 15 Mar 2024 03:16

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Contributors

Author: Thomas Powles
Author: Shah-Jalal Sarker Foreshew
Author: Jonathan Shamash
Author: Naveed Sarwar
Author: Simon Crabb ORCID iD
Author: Anju Sahdev
Author: Jude Nixon
Author: Louise Lim
Author: Ashish Pungaliya
Author: Abigail Foreshaw
Author: Rachel Davies
Author: Michelle Greenwood
Author: Peter Wilson
Author: Simon Pacey
Author: Myra Galazi
Author: Robert Jones
Author: Simon Chowdhury

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